
免疫监控指导治疗脐血移植后急性移植物抗宿主病一例并文献复习
吴正宙, 詹丽萍, 阙丽萍, 吴晓君, 徐宏贵, 黄科
新医学 ›› 2024, Vol. 55 ›› Issue (3) : 208-213.
免疫监控指导治疗脐血移植后急性移植物抗宿主病一例并文献复习
Treatment of acute graft-versus-host disease after umbilical cord blood transplantation under the guidance of immune monitoring: a case report and literature review
目的 探讨以皮疹为主要表现的急性移植物抗宿主病(aGVHD)在免疫监控指导下的精准诊疗效果。方法 回顾1例因高危急性髓系白血病接受非血缘脐血移植、其后出现顽固性皮疹的患儿的临床资料及诊治过程,以“造血干细胞移植”“免疫重建”和“急性移植物抗宿主病”的中英文为检索词,对以下数据库的相关论文进行检索:PubMed、Web of Science、CNKI、万方数据知识服务平台,收集检索到的病例资料并进行分析。结果 该例1岁9月龄女性患儿成功获得造血重建,移植后22 d患儿头部、后颈部出现密集红色丘疹(面积约19%)、瘙痒明显,口服他克莫司、外用激素类药物后皮疹无好转(面积>90%),此时监测CD3+细胞、CD8+细胞、CD3+CD69+细胞、CD3+HLA-DR+细胞比例明显升高,调节性T细胞(Treg)比例下降。免疫指标支持T淋巴细胞活化,考虑Ⅱ度aGVHD(皮肤3级),遂予加强免疫抑制治疗方案。期间患儿皮疹有消退,但仍反复,并伴皮肤明显脱屑,复查CD3+细胞、CD8+细胞、CD3+HLA-DR+细胞比例仍偏高,遂再次调整治疗方案、加强抗排斥,患儿皮肤aGVHD好转。定期监测原发病完全缓解、植入比例100%、免疫重建稳定,随访至移植后32个月,患儿无病存活。检索到相关文献9 篇,均论证了早期CD3+细胞、CD8+细胞、活化T淋巴细胞比例升高以及Treg下调与aGVHD发生相关。结论 对异基因造血干细胞移植术后患者的免疫状态进行动态监测,有利于评估其免疫重建情况及疾病状态(如aGVHD),有助于制定合理的免疫抑制治疗方案,使患者获得良好预后。
Objective To explore the effect of the precise diagnosis and treatment of a case of acute graft-versus-host disease (aGVHD) with rash as the main manifestation under the guidance of immune monitoring. Methods Clinical data and diagnosis and treatment of a child with high-risk acute myeloid leukemia who developed intractable rash after receiving unrelated umbilical cord blood transplantation were retrospectively analyzed. Using the keywords of “hematopoietic stem cell transplantation”“immune reconstitution” and “acute graft-versus-host disease”, relevant literatures were searched from PubMed, Web of Science, CNKI and Wanfang databases, and relevant cases were collected and analyzed. Results Hematopoietic reconstruction was successfully achieved in this 1 year 9 months old girl. On day 22 after transplantation, the skin of head and back neck of the patient showed dense red papules (approximately 19% in area), with obvious itching. Under the treatment of oral tacrolimus and topical hormone drugs, the rash was not alleviated (area>90%). Meanwhile, the proportion of CD3+ cells, CD8+ cells, CD3+CD69+cells and CD3+HLA-DR+cells was significantly increased, and the proportion of Treg cells was decreased. The immune indexes supported T lymphocyte activation, then diagnosis of gradeⅡaGVHD (skin grade 3) was made, and the immunosuppressive regimen was strengthened. During this period, the skin rash of the child subsided, but recurred, and accompanied by obvious skin desquamation. The proportion of CD3+ cells, CD8+ cells, and CD3+HLA-DR+cells remains relatively high, supporting the diagnosis of aGVHD. Therefore, the anti-GVHD regimen was adjusted and strengthened, and the aGVHD of the child’s skin was mitigated. Regular monitoring showed that the primary disease was completely relieved, the implantation rate was 100%, and the immune reconstitution was stable. During 32-month follow-up after transplantation, the child obtained disease-free survival. Nine relevant literatures were retrieved, all of which demonstrated that the increased proportion of early CD3+ cells, CD8+ cells, activated T lymphocytes and Treg downregulation were associated with the occurrence of aGVHD. Conclusions The dynamic monitoring of the immune status of patients after allogeneic hematopoietic stem cell transplantation is helpful to evaluate their immune reconstitution and disease status (such as, aGVHD), thereby assisting clinicians to formulate a reasonable immunosuppressive regimen and bring favorable prognosis to patients.
造血干细胞移植 / 脐血 / 急性移植物抗宿主病 / 免疫监控 / 免疫重建 {{custom_keyword}} /
Hematopoietic stem cell transplantation / Cord blood / Acute graft-versus-host disease / Immune monitoring / Immune reconstitution {{custom_keyword}} /
表1 一例以顽固性皮疹为主要表现的aGVHD患儿移植后不同时间段的免疫细胞百分比(%) |
时 间 | CD3+细胞 | CD4+细胞 | CD8+细胞 | CD19+细胞 | CD16+CD56+ 细胞 | Treg/CD4+ | CD3+CD69+细胞 | CD3+HLA-DR+细胞 |
---|---|---|---|---|---|---|---|---|
移植前21 d | 96.35 | 42.45 | 40.94 | 0.04 | 3.42 | 18.82 | 0.6 | 26.88 |
移植后14 d | 75.18 | 17.26 | 51.6 | NT | NT | NT | 5.57 | 77.39 |
移植后21 d | 48.67 | 14.71 | 30.34 | NT | NT | NT | 6.45 | 60.34 |
移植后30 d | 84.9 | 20.1 | 64.38 | 0.43 | 11.53 | 7.63 | 1.35 | 90.31 |
移植后40 d | 80.08 | 14.38 | 63.04 | NT | NT | NT | 2.79 | 89.83 |
移植后47 d | 82.11 | 27.54 | 50.43 | NT | NT | NT | 2.32 | 73.33 |
移植后60 d | 61.01 | 17.09 | 43.21 | 0.81 | 34.7 | 9.22 | 1.66 | 81.29 |
移植后90 d | 39.31 | 18.22 | 20.22 | 44.03 | 12.2 | 24.26 | NT | NT |
移植后120 d | 43.38 | 21.5 | 18.43 | NT | NT | 9.91 | 2.99 | 74.21 |
移植后180 d | 51.16 | 24.44 | 22.31 | 39.87 | 7.99 | NT | NT | NT |
移植后210 d | 44.39 | 20.68 | 19.8 | 48.23 | 6.53 | NT | NT | NT |
移植后270 d | 61.49 | 27.15 | 27.97 | 25.72 | 12.07 | 8.49 | NT | NT |
移植后360 d | 59.78 | 29.76 | 22.94 | 31.48 | 7.98 | 8.4 | NT | NT |
注: CD3+细胞参考值范围为56%~75%,CD4+细胞为28%~47%,CD8+细胞为16%~30%,CD19+细胞为14%~33%,CD16+CD56+细胞为4%~17%,Treg/CD4+为4.5%~6.2%,CD3+CD69+细胞为1.2%~3%,CD3+HLA-DR+细胞为1%~3%; NT为未检测。 |
表2 一例以顽固性皮疹为主要表现的aGVHD患儿移植后不同时间段的免疫细胞绝对值结果 |
时 间 | CD3+细胞 | CD4+细胞 | CD8+细胞 | CD19+细胞 | CD16+CD56+细胞 | Treg | CD4+CD45RA+细胞 | CD4+CD45RA+PTK-7+细胞 |
---|---|---|---|---|---|---|---|---|
移植前21 d | 925 | 393 | 379 | 0 | 33 | 74 | 218 | 0.8 |
移植后14 d | 128 | 22 | 66 | NT | NT | NT | NT | NT |
移植后21 d | 122 | 18 | 37 | NT | NT | NT | NT | NT |
移植后30 d | 1 282 | 302 | 972 | 7 | 174 | 23 | NT | NT |
移植后40 d | 640 | 92 | 403 | NT | NT | NT | NT | NT |
移植后47 d | 345 | 95 | 174 | NT | NT | NT | NT | NT |
移植后60 d | 713 | 200 | 505 | 9 | 405 | 18 | 0 | 0 |
移植后90 d | 328 | 152 | 169 | 368 | 102 | 37 | 12 | 0.3 |
移植后120 d | 508 | 109 | 94 | NT | NT | 11 | NT | NT |
移植后180 d | 635 | 303 | 277 | 495 | 99 | NT | 59 | 2 |
移植后210 d | 1 172 | 242 | 232 | 600 | 172 | NT | NT | NT |
移植后270 d | 1 613 | 712 | 733 | 674 | 317 | 61 | 315 | 28 |
移植后360 d | 1 431 | 714 | 549 | 753 | 191 | 59 | 276 | 9 |
注: CD3+细胞参考值范围为690~2 540,CD4+细胞为410~1 590,CD8+细胞为190~1 140,CD19+细胞为537~1 464,CD16+CD56+细胞为90~660,NT为未检测。 |
表3 文献检索免疫重建过程中各免疫细胞亚群与aGVHD的关系 |
第一作者 | 年龄组 | 免疫细胞亚群 | 与aGVHD的相互作用 |
---|---|---|---|
沈耀耀[16] | 儿童及成人 | CD3+细胞 | 移植后3个月内发生Ⅲ~Ⅳ度aGVHD患者的CD3+细胞明显升高 |
Paz Morante M[18] | 成人 | CD3+CD69+细胞 | CD3+CD69+细胞比例在aGVHD发生早期明显升高 |
Dekker L[22] | 儿童 | CD4+细胞 | 较高的CD4+细胞数量可减轻aGVHD |
de Koning C[23] | 儿童 | CD4+细胞 | aGVHD后CD4+细胞的早期恢复预示着更好的预后 |
PodgornyPJ[17] | 成人 | CD8+细胞 | 早期恢复与aGVHD风险增加相关 |
Khandelwal P[24] | 儿童及成人 | CD8+细胞 | CD8+效应记忆T(TEM)细胞明显升高可以预测aGVHD的发生 |
Magenau J M[20] | 不详 | Treg | aGVHD患者中Treg显著下降,且aGVHD等级越高,该细胞数下降越明显 |
Dekker L[22] | 不详 | Treg | aGVHD患者中Treg显著下降,且aGVHD等级越高,该细胞数下降越明显 |
van der Maas N G[25] | 儿童 | B淋巴细胞 | 早期恢复预示aGVHD风险降低 |
Waller E K[26] | 不详 | B淋巴细胞 | 有Ⅱ~Ⅳ度aGvHD病史的患者B淋巴细胞数量更低 |
[1] |
Graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) is associated with considerable morbidity and mortality, particularly in patients who do not respond to primary therapy, which usually consists of glucocorticoids (steroids). Approaches to therapy of acute GVHD refractory to "standard" doses of steroids have ranged from increasing the dose of steroids to the addition of polyclonal or monoclonal antibodies, the use of immunotoxins, additional immunosuppressive/chemotherapeutic interventions, phototherapy, and other means. While many pilot studies have yielded encouraging response rates, in most of these studies long-term survival was not improved in comparison with that seen with the use of steroids alone. A major reason for failure has been the high rate of infections, including invasive fungal, bacterial, and viral infections. It is difficult to conduct controlled prospective trials in the setting of steroid-refractory GVHD, and a custom-tailored therapy dependent upon the time after HCT, specific organ manifestations of GVHD, and severity is appropriate. All patients being treated for GVHD should also receive intensive prophylaxis against infectious complications.
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[2] |
The incidence of graft-versus-host disease (GVHD) after cord blood (CB) transplantation (CBT) is lower than expected given the marked degree of human leukocyte antigen (HLA)-mismatch of CB grafts. While the exact mechanism that underlies this biology remains unclear, it is hypothesized to be due to the low number of mostly immature T-cells infused as part of the graft1,2, and increased tolerance of CB-derived lymphocytes induced by the state of pregnancy. Nevertheless, acute GVHD (aGVHD) is a significant complication of CBT. In contrast, the incidence of chronic GVHD (cGVHD) following CBT is lower than what is observed following matched related or unrelated donor HSC transplantation (HSCT)3-6. This review outlines the guidelines for the prevention and management of acute and chronic GVHD following CBT.Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.
{{custom_citation.content}}
{{custom_citation.annotation}}
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[3] |
{{custom_citation.content}}
{{custom_citation.annotation}}
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[4] |
Acute graft-versus-host disease (GVHD) is a common immune complication that can occur after allogeneic haematopoietic cell transplantation (alloHCT). Acute GVHD is a major health problem in these patients, and is associated with high morbidity and mortality. Acute GVHD is caused by the recognition and the destruction of the recipient tissues and organs by the donor immune effector cells. This condition usually occurs within the first 3 months after alloHCT, but later onset is possible. Targeted organs include the skin, the lower and upper gastrointestinal tract and the liver. Diagnosis is mainly based on clinical examination, and complementary examinations are performed to exclude differential diagnoses. Preventive treatment for acute GVHD is administered to all patients who receive alloHCT, although it is not always effective. Steroids are used for first-line treatment, and the Janus kinase 2 (JAK2) inhibitor ruxolitinib is second-line treatment. No validated treatments are available for acute GVHD that is refractory to steroids and ruxolitinib, and therefore it remains an unmet medical need.© 2023. Springer Nature Limited.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
[5] |
中华医学会血液学分会干细胞应用学组. 中国异基因造血干细胞移植治疗血液系统疾病专家共识(Ⅲ)——急性移植物抗宿主病(2020年版)[J]. 中华血液学杂志, 2020, 41(7): 529-536.
Stem Cell Application Group, Chinese Society of Hematology, Chinese Medical Association. Chinese consensus of allogeneic hematopoietic stem cell transplantation for hematological disease (Ⅲ)——acute graft-versus-host disease (2020)[J]. Chin J Hematol, 2020, 41(7): 529-536.
{{custom_citation.content}}
{{custom_citation.annotation}}
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[6] |
{{custom_citation.content}}
{{custom_citation.annotation}}
|
[7] |
Immune reconstitution (IR) after allogeneic haematopoietic cell transplantation (HCT) represents a central determinant of the clinical post-transplant course, since the majority of transplant-related outcome parameters such as graft-vs.-host disease (GvHD), infectious complications, and relapse are related to the velocity, quantity and quality of immune cell recovery. Younger age at transplant has been identified as the most important positive prognostic factor for favourable IR post-transplant and, indeed, accelerated immune cell recovery in children is most likely the pivotal contributing factor to lower incidences of GvHD and infectious complications in paediatric allogeneic HCT. Although our knowledge about the mechanisms of IR has significantly increased over the recent years, strategies to influence IR are just evolving. In this review, we will discuss different patterns of IR during various time points post-transplant and their impact on outcome. Besides IR patterns and cellular phenotypes, recovery of antigen-specific immune cells, for example virus-specific T cells, has recently gained increasing interest, as certain threshold levels of antigen-specific T cells seem to confer protection against severe viral disease courses. In contrast, the association between IR and a possible graft-vs. leukaemia effect is less well-understood. Finally, we will present current concepts of how to improve IR and how this could change transplant procedures in the near future.
{{custom_citation.content}}
{{custom_citation.annotation}}
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[8] |
The timely reconstitution and regain of function of a donor-derived immune system is of utmost importance for the recovery and long-term survival of patients after allogeneic hematopoietic stem cell transplantation (HSCT). Of note, new developments such as umbilical cord blood or haploidentical grafts were associated with prolonged immunodeficiency due to delayed immune reconstitution, raising the need for better understanding and enhancing the process of immune reconstitution and finding strategies to further optimize these transplant procedures. Immune reconstitution post-HSCT occurs in several phases, innate immunity being the first to regain function. The slow T cell reconstitution is regarded as primarily responsible for deleterious infections with latent viruses or fungi, occurrence of graft-versus-host disease, and relapse. Here we aim to summarize the major steps of the adaptive immune reconstitution and will discuss the importance of immune balance in patients after HSCT.
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|
[9] |
{{custom_citation.content}}
{{custom_citation.annotation}}
|
[10] |
{{custom_citation.content}}
{{custom_citation.annotation}}
|
[11] |
{{custom_citation.content}}
{{custom_citation.annotation}}
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[12] |
Effective control of the graft-versus-host disease (GVHD) and immune reconstitution are crucial in improving the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) as well as the quality of life of the transplant survivors. Recent basic and clinical studies have deepened our understanding of the mechanisms of the immunological sequelae of HSCT, GVHD, and compromised immune systems. Based on the findings, various novel approaches have also been developed and tested clinically. However, further studies are necessary to develop therapeutic strategies with significant clinical benefits.Copyright Ⓒ2023 Asia-Pacific Blood and Marrow Transplantation Group (APBMT).
{{custom_citation.content}}
{{custom_citation.annotation}}
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[13] |
Mass cytometry, or Cytometry by Time-Of-Flight, is a powerful new platform for high-dimensional single-cell analysis of the immune system. It enables the simultaneous measurement of over 40 markers on individual cells through the use of monoclonal antibodies conjugated to rare-earth heavy-metal isotopes. In contrast to the fluorochromes used in conventional flow cytometry, metal isotopes display minimal signal overlap when resolved by single-cell mass spectrometry. This review focuses on the potential of mass cytometry as a novel technology for studying immune reconstitution in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Reconstitution of a healthy donor-derived immune system after HSCT involves the coordinated regeneration of innate and adaptive immune cell subsets in the recipient. Mass cytometry presents an opportunity to investigate immune reconstitution post-HSCT from a systems-level perspective, by allowing the phenotypic and functional features of multiple cell populations to be assessed simultaneously. This review explores the current knowledge of immune reconstitution in HSCT recipients and highlights recent mass cytometry studies contributing to the field.
{{custom_citation.content}}
{{custom_citation.annotation}}
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[14] |
黄盼盼, 张爱梅, 张翠萍, 等. 外周血干细胞移植与非血缘脐带血移植的患者免疫重建规律的比较[J]. 中华检验医学杂志, 2021, 44(12): 1138-1144.
{{custom_citation.content}}
{{custom_citation.annotation}}
|
[15] |
We evaluated the kinetics of immune reconstitution (IR) after allogeneic hematopoietic cell transplantation (HSCT) and analyzed the clinical effect of IR on posttransplant outcomes. Absolute lymphocyte and its subset counts were measured using flow cytometry on days 28, 100, 180, 365, and 730 after transplantation in 358 adult patients who underwent HSCT between 2009 and 2017. On day 100 after HSCT, 310 surviving patients were analyzed. Bone marrow transplantation (BMT), peripheral blood stem cell transplantation (PBSCT), and cord blood transplantation (CBT) were performed in 119, 55, and 136 patients, respectively. Mature B-cell and differentiated natural killer (NK) cell subset counts significantly increased after CBT. The 2-year overall survival (OS), nonrelapse mortality (NRM), cumulative incidence of relapse, and chronic GVHD in BMT, PBSCT, and CBT were 62%, 67%, and 76% (P =.021); 17%, 17%, and 13% (P =.82); 33%, 40%, and 27% (P =.063); and 43%, 45%, and 28% (P =.025), respectively. Multivariate analysis showed that higher CD16+CD57- NK cell counts correlated with lower disease relapse, whereas higher CD20+ B-cell counts correlated with lower NRM. OS-favoring factors were higher CD16+CD57- NK cell count (hazard ratio, 0.36; 95% confidence interval, 0.22-0.60; P <.001) and CD20+ B-cell count (hazard ratio, 0.53; 95% confidence interval, 0.30-0.93; P <.001) and lower Disease Risk/HCT-Specific Comorbidity index score. Collective contribution of graft source-specific and event-related immune reconstitution might yield better posttransplant outcomes in CBT.© 2020 by The American Society of Hematology.
{{custom_citation.content}}
{{custom_citation.annotation}}
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[16] |
沈耀耀, 刘跃均, 吴德沛, 等. 异基因造血干细胞移植后免疫重建的临床研究及急性移植物抗宿主病的危险因素分析[J]. 白血病·淋巴瘤, 2015, 24(6): 346-351.
{{custom_citation.content}}
{{custom_citation.annotation}}
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[17] |
{{custom_citation.content}}
{{custom_citation.annotation}}
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[18] |
During the effector phase of graft-versus-host disease (GvHD) response, donor T cells play an essential role and they are believed to change the expression of activation and co-stimulatory markers associated with functional alloreactivity. We analysed the expression of CD25, CD69, HLA-DR, CD154 and CD134 on CD4+ and CD8+ T cells by flow cytometry during acute GvHD (aGvHD) in 24 patients receiving human leucocyte antigen (HLA)-identical stem cell transplants. Expression of these molecules in nine patients with stages I-IV aGvHD was compared with 15 patients without aGvHD (n = 15). Serial analysis showed that peripheral blood of aGvHD patients presented a significant increase of CD4+ CD25+ cells (P < 0.03), CD4+ CD69+ (P < 0.04) and CD4+ CD134+ cells (P < 0.01). Additionally, there was a significant increase in CD8+ cells expressing CD134 (P = 0.007) and CD154 (P = 0.02). After resolution of aGvHD, the increased expression of these molecules returned to values comparable to patients without aGvHD. Only two of the 15 patients without clinical signs of aGvHD presented activated T cells that could not be attributed to development of aGvHD. In summary, our data show that multiple activation molecules are preferentially up-regulated on CD4+ and CD8+ T cells from patients with aGvHD. These patients had a significant increase in the expression of the co-stimulatory molecules CD134 and CD154.
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[19] |
Despite significant advances in treatment and prevention, graft-versus-host disease (GVHD) still represents the main cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Thus, considerable research efforts have been made to find and validate reliable biomarkers for diagnosis, prognosis, and risk stratification of GVHD.In this review the most recent evidences on different types of biomarkers studied for GVHD, such as genetic, plasmatic, cellular markers, and those associated with microbiome, were summarized. A comprehensive search of peer-review literature was performed in PubMed including meta-analysis, preclinical and clinical trials, using the terms: cellular and plasma biomarkers, graft-versus-host disease, cytokines, and allogeneic hematopoietic stem cell transplantation.In the near future, several validated biomarkers will be available to help clinicians in the diagnosis of GVHD, the identification of patients at high risk of GVHD development and in patients' stratification according to its severity. Then, immunosuppressive treatment could be tailored to each patient's real needs. However, more efforts are needed to achieve this goal. Although most of the proposed biomarkers currently lack validation with large-scale clinical data, their study led to improved knowledge of the biological basis of GVHD, and ultimately to implementation of GHVD treatment.
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[20] |
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[21] |
In comparison with allogeneic stem cell transplantation (alloHSCT) with other stem cell sources, umbilical cord blood transplantation (UCBT) was traditionally associated with increased risk of infections, particularly during the first 3 months after transplantation. Longitudinal studies of immune monitoring reported peculiar patterns of T- and B-cell recovery in the peripheral blood of UCB recipients during the first months post-transplantation. Overall, current data suggest delayed reconstitution of naive and memory CD4 and CD8 T-cell pools after UCBT. This is particularly true for adult recipients and for patients who received T-cell depleting approaches before the transplantation. Such delayed T-cell recovery may increase susceptibility of UCB recipients for developing opportunistic infections and viral reactivations. Regarding B-cell recovery, UCBT was associated with accelerated B-lymphopoiesis. Recent studies also reported evidence for faster functional memory B-cell recovery in UCB recipients. In this article, we briefly review T- and B-cell reconstitution after alloHSCT, with emphasis on peculiarities observed after UCBT. We further put these data in lines with risks of infections after UCBT.
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[22] |
Allogeneic (allo) hematopoietic cell transplantation (HCT) is the only curative treatment option for patients suffering from chemotherapy-refractory or relapsed hematological malignancies. The occurrence of morbidity and mortality after allo-HCT is still high. This is partly correlated with the immunological recovery of the T cell subsets, of which the dynamics and relations to complications are still poorly understood. Detailed information on T cell subset recovery is crucial to provide tools for better prediction and modulation of adverse events. Here, we review the current knowledge regarding CD4+ and CD8+ T cells, γδ T cells, iNKT cells, Treg cells, MAIT cells and naive and memory T cell reconstitution, as well as their relations to outcome, considering different cell sources and immunosuppressive therapies. We conclude that the T cell subsets reconstitute in different ways and are associated with distinct adverse and beneficial events; however, adequate reconstitution of all the subsets is associated with better overall survival. Although the exact mechanisms involved in the reconstitution of each T cell subset and their associations with allo-HCT outcome need to be further elucidated, the data and suggestions presented here point towards the development of individualized approaches to improve their reconstitution. This includes the modulation of immunotherapeutic interventions based on more detailed immune monitoring, aiming to improve overall survival changes.
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[23] |
Acute graft-versus-host-Disease (aGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). We previously showed that early CD4+ T-cell immune reconstitution (IR; CD4+ IR) predicts survival after HCT. Here, we studied the relation between CD4+ IR and survival in patients developing aGVHD. Pediatric patients undergoing first allogeneic HCT at University Medical Center Utrecht (UMC)/Princess Máxima Center (PMC) or Memorial Sloan Kettering Cancer Center (MSK) were included. Primary outcomes were nonrelapse mortality (NRM) and overall survival (OS), stratified for aGVHD and CD4+ IR, defined as ≥50 CD4+ T cells per μL within 100 days after HCT or before aGVHD onset. Multivariate and time-to-event Cox proportional hazards models were applied, and 591 patients (UMC/PMC, n = 276; MSK, n = 315) were included. NRM in patients with grade 3 to 4 aGVHD with or without CD4+ IR within 100 days after HCT was 30% vs 80% (P =.02) at UMC/PMC and 5% vs 67% (P =.02) at MSK. This was associated with lower OS without CD4+ IR (UMC/PMC, 61% vs 20%; P =.04; MSK, 75% vs 33%; P =.12). Inadequate CD4+ IR before aGVHD onset was associated with significantly higher NRM (74% vs 12%; P <.001) and inferior OS (24% vs 78%; P <.001). In this retrospective analysis, we demonstrate that early CD4+ IR, a simple and robust marker predictive of outcomes after HCT, is associated with survival after moderate to severe aGVHD. This association must be confirmed prospectively but suggests strategies to improve T-cell recovery after HCT may influence survival in patients developing aGVHD.© 2021 by The American Society of Hematology.
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[24] |
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[25] |
B cell reconstitution after hematopoietic stem cell transplantation (HSCT) is variable and influenced by different patient, donor, and treatment related factors. In this review we describe B cell reconstitution after pediatric allogeneic HST, including the kinetics of reconstitution of the different B cell subsets and the development of the B cell repertoire, and discuss the influencing factors. Observational studies show important roles for stem cell source, conditioning regimen, and graft vs. host disease in B cell reconstitution. In addition, B cell recovery can play an important role in post-transplant infections and vaccine responses to encapsulated bacteria, such as pneumococcus. A substantial number of patients experience impaired B cell function and/or dependency on Ig substitution after allogeneic HSCT. The underlying mechanisms are largely unresolved. The integrated aspects of B cell recovery after HSCT, especially BCR repertoire reconstitution, are awaiting further investigation using modern techniques in order to gain more insight into B cell reconstitution and to develop strategies to improve humoral immunity after allogeneic HSCT.
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[26] |
The clinical utility of monitoring immune reconstitution after allotransplant was evaluated using data from Blood and Marrow Transplant Clinical Trials Network BMT CTN 0201 (NCT00075816), a multicenter randomized study of unrelated donor bone marrow (BM) vs granulocyte colony-stimulating factor (G-CSF)-mobilized blood stem cell (G-PB) grafts. Among 410 patients with posttransplant flow cytometry measurements of immune cell subsets, recipients of G-PB grafts had faster T-cell reconstitution than BM recipients, including more naive CD4 T cells and T-cell receptor excision circle-positive CD4 and CD8 T cells at 3 months, consistent with better thymic function. Faster reconstitution of CD4 T cells and naive CD4 T cells at 1 month and CD8 T cells at 3 months predicted more chronic graft-versus-host disease (GVHD) but better survival in G-PB recipients, but consistent associations of T-cell amounts with GVHD or survival were not seen in BM recipients. In contrast, a higher number of classical dendritic cells (cDCs) in blood samples at 3 months predicted better survival in BM recipients. Functional T-cell immunity measured in vitro by cytokine secretion in response to stimulation with cytomegalovirus peptides was similar when comparing blood samples from BM and G-PB recipients, but the degree to which acute GVHD suppressed immune reconstitution varied according to graft source. BM, but not G-PB, recipients with a history of grades 2-4 acute GVHD had lower numbers of B cells, plasmacytoid dendritic cells, and cDCs at 3 months. Thus, early measurements of T-cell reconstitution are predictive cellular biomarkers for long-term survival and response to GVHD therapy in G-PB recipients, whereas more robust DC reconstitution predicted better survival in BM recipients.© 2019 by The American Society of Hematology.
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